Synthesis of C2 Substituted Benzothiophenes via an Interrupted Pummerer/[3,3]‐Sigmatropic/1,2‐Migration Cascade of Benzothiophene S‐Oxides

Abstract

Functionalized benzothiophenes are important scaffolds found in molecules with wide ranging biological activity and in organic materials. We describe an efficient, metal-free synthesis of C2 arylated, allylated, and propargylated benzothiophenes. The reaction utilizes synthetically unexplored yet readily accessible benzothiophene S-oxides and phenols, allyl-, or propargyl silanes in a unique cascade sequence. An interrupted Pummerer reaction between benzothiophene S-oxides and the coupling partners yields sulfonium salts that lack aromaticity and therefore allow facile [3,3]-sigmatropic rearrangement. The subsequently generated benzothiophenium salts undergo a previously unexplored 1,2-migration to access C2 functionalized benzothiophenes.

The Interrupted Pummerer Reaction in a Sulfoxide‐Catalyzed Oxidative Coupling of 2‐Naphthols

“…Based on the above results, and our previous studies,, we propose the catalytic cycle set out in Scheme A. Benzothiophene S ‐oxide 3 a reacts with TFAA to form activated sulfoxide II , which we have observed by NMR (see the Supporting Information) . Subsequently, 2‐naphthols 1 a react through oxygen with II in an interrupted Pummerer process to form aryloxysulfonium salts I ,.…”

“…For example, selective oxidation and electrophilic activation of sulfur must be possible in the presence of other nucleophiles, and interrupted Pummerer reactivity must out‐run side reactions (e.g. classical Pummerer chemistry) and rearrangements of sulfonium intermediates A and B ,–…”

“…To our knowledge no metal‐free, organocatalytic synthesis of BINOLs has been reported. The process constitutes a rare example of a catalytic Pummerer process, uses synthetically under‐explored benzothiophene S ‐oxides,, and employs inexpensive H 2 O 2 as the terminal oxidant. The high functional group compatibility of the process has been exploited in the synthesis of (±)‐nigerone and related natural products.…”

“…Finally, benzothiophene S ‐oxides 3 f and 3 g bearing bulky substituents at C3 proved less effective in the coupling than 3 a . The C3 substituent is likely to play a role in disfavoring the competing rearrangement of aryloxysulfonium salts I ,…”

“…For a catalytic process, chemoselective oxidation of the sulfide byproduct, to the sulfoxide and not the sulfone, by a convenient terminal oxidant in the presence of the other nucleophilic reaction components is crucial. H 2 O 2 and TFAA, were added in one portion to a solution of 2‐naphthol ( 1 a ) and 10 mol % of sulfide 3 a′ . Pleasingly, 2 a was obtained in 45 % yield (Table , entry 1).…”